1. Field of the Invention
The present invention is directed to delivery systems, which stabilize surface active therapeutic agents, or those therapeutic agents which obtain surface active properties in a delivery system. These systems are suitable for use in the vaginal cavity, as well as other mucosal cavities of the body. The invention is additionally concerned with preparations demonstrating a modified, controlled, extended or sustained release of the active and/or therapeutic agent and a minimal number of administrations to produce efficacy upon administration of said delivery system.
2. Description of the Related Art
One significant aspect of medicine is the treatment of the female reproductive system for the prevention, treatment, mitigation, diagnosis and cure of diseases and the prevention of conception. Usually, this involves the delivery of active agents to the vaginal cavity and its environs. Systems to affect the delivery of such agents are usually in the form of gels, foams, creams, suppositories and quick dissolving tablets. These delivery systems, regardless of formulation or method of manufacture, have not reliably demonstrated the ability to deliver active agents in a controlled manner with lower systemic absorption within the vaginal cavity for long periods of time, and particularly for 12 hours or longer. This may be attributed to the vaginal cavity environment as well as to the known formulations designed to administer drugs thereto.
The vaginal cavity is subject to conditions rendering it a target for disease and infection; however, as previously noted, it is extremely difficult to deliver an active agent to this area for an extended period of time. The vaginal cavity exhibits an aqueous environment containing secreting glands whose fluids create an acidic pH in the range of 4.5 to 5.5. The environment of the vagina is conducive to the growth of various microbes, such as bacteria, fungi, yeast and other microorganisms since it is warm, moist and dark. It is also the vestibule for menstrual debris and the residual seminal fluid from sexual intercourse. The crevices of the vaginal cavity facilitate the retention of undesirable bacteria, fungi, yeast and other microorganisms, as well as the debris from menstruation and sexual intercourse. The vaginal cavity is also subject to considerable physical deformation, such as during sexual intercourse or during the insertion of tampons.
Active agents having pharmaceutical qualities have been developed and approved for use in the treatment of conditions and diseases of the vaginal cavity and the prevention of conception. These include fungicides, antibiotics, spermicides, etc. Although pharmaceutically active agents have been developed, it has been difficult to achieve optimal potential effectiveness from these agents due to the inadequacy of currently available drug delivery systems. The majority of gels, foams, creams, suppositories and tablets presently used as vaginal delivery systems can breakdown almost immediately following insertion into the vaginal cavity and have minimal bioadherence to the vaginal walls. Often, this is believed to be due to their water miscibility and/or their lack of physical stability at 37 degrees C. (body temperature). Further, the nature of the active/therapeutic agent itself can cause the delivery system to deteriorate. This may be due to the fact that the active/therapeutic agent possesses surface active properties or obtains surface active characteristics when placed into various delivery systems known in the art. Examples of vaginal delivery systems, can be found in U.S. Pat. Nos. 5,055,303 and 5,266,329, both of which are incorporated herein by reference in their entirety.
Many known systems exhibit limited effectiveness since they rapidly release their active agents in an uncontrolled manner and rapid manner. Further, conventional systems also result in a relatively high systemic absorption of the active agent, which may be due in part to the instability of the system. This level of systemic absorption is such that in a plasma concentration versus time curve will result in an area under the curve (AUC) of at least about 200 ng/mL·hr. Typically, the AUC will be much higher, e.g., at least about 300 to as much as 4,500 ng/mL·hr. Further, conventional dosage forms are frequently discharged as an offensive leakage and drippage along with the minute vaginal secretions that are a normal physiological function. One particular clindamycin phosphate vaginal formulation currently known in the art is sold as Cleocin® and manufactured by Pharmacia & Upjohn.
The pharmacology of clindamycin is known in the art. See for example, Aroutcheva, A., et al., The inhibitory effect of clindamycin on Lactobacillus in vitro., Infectious diseases in Obstetrics and Gynecology, 9, 2001, (4), 239-44; and Muli, F., et al., Use of continuous-culture biofilm system to study the antimicrobial susceptibilities of Gardnerella vaginalis and Lactobacillus acidophilus., Antimicrobial agents and chemotherapy, 42, June 1998, (6) 1428-32, both of which are incorporated herein by reference in their entirety.
The toxicology of clindamycin is also well known in the art. See for example, Gray, J. E., et al., The Oral Toxicity of Clindamycin in Laboratory Animals., Toxicology and Applied Pharmacology 21, 1972, 516-531; and Bollert, J. A., et al., Teratogenicity and Neonatal Toxicity of Clindamycin 2-Phosphate in Laboratory Animals., Toxicology and Applied Pharmacology 27, 322-329, both of which are incorporated herein by reference in their entirety.
A controlled release system delivers the active agent to the site of action, activity, expected activity, absorption or use in a predetermined manner. This contrasts with conventional immediate release systems, which require frequent repetitive dosing in order to achieve the desired level of active agent. An unexpected advantage of a controlled release system is that the drug is administered fewer times a day or fewer times during the therapy period than conventional systems since the drug level in the vaginal cavity is maintained at a constant or controlled level. Unfortunately, the controlled release systems known in the art do not affect the total number of days that are required to treat a condition.
The present invention is advantageous because it provides a system for the delivery of an active agent in a controlled manner in the vaginal cavity for an extended period of at least several days. The vaginal drug delivery system may take the form of a multi-phase liquid or semi-solid, which is easily introduced into the vaginal cavity. Additionally, due to the bioadhesive nature of the delivery system, the material introduced into the vaginal cavity does not seep or seepage is reduced from this body cavity in an offensive manner. In comparison to conventional vaginal drug delivery with conventional creams and ointments, the present technology is further advantageous in that it reduces the number of administrations needed to obtain efficacy for active agents such as, clindamycin phosphate. The conventional clindamycin phosphate vaginal cream (Cleocin™ Vaginal Cream) needs to be administered nightly for 7 consecutive nights in order to affect a cure. The present technology needs to be administered only once to affect the same cure.
Besides advantages regarding the convenience afforded by a single dose administration, the present technology is also characterized with providing a highly cost effective treatment for vaginal infections in that only one applicator is needed to do the treatment as contrasted to 7 applicators needed for the conventional cream product. Additionally, since only 100 mg of active drug (2% of a 5.0 gram application) is needed with the present technology, as compared to 700 mg of active drug required for a full dose of therapy with the conventional cream (2% of 5.0 gram times 7 applications) a significant savings in active drug and excipients is also achieved.